Olfactory copy number association with age at onset of Alzheimer disease.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Erratum in

Neurology. 2011 May 31;76(22):1945.

Abstract

OBJECTIVES:

Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD.

RESULTS:

The discovery sample identified a chromosomal segment on 14q11.2 (19.3-19.5 Mb, NCBI build 36, UCSC hg18 March 2006) as a region of interest (genome-wide adjusted p = 0.032) for association with AAO of AD. This region encompasses a cluster of olfactory receptors. The replication sample confirmed the association (p = 0.035). The association was found for each APOE4 gene dosage (0, 1, and 2).

CONCLUSION:

High copy number in the olfactory receptor region on 14q11.2 is associated with younger age at onset of AD.

(A) The multiallelic variation_0316 (black bars) detected in 35% of the subjects in relation to known copy number variants (CNVs) (orange bars). The genomic coordinates on chromosome 14 are expressed in Mb. The hashed red bars on the genomic coordinate line are olfactory receptor genes and the black bars represent pseudogenes. (B) Three subjects ascertained on both the array comparative genome hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, having 2, 3, and 4 copy genotypes in the 3 respective panels. The aCGH data are plotted by log_2 ratio and the SNP array data are visualized as copy number state after segmentation with the HMM algorithm. Multiplex ligation-dependent probe amplification assays are shown in (C) for 3 HapMap samples harboring 2, 3, and 4 copy genotypes (equivalent of panel B). Confirmation of gene dosage and genomic location by fluorescent in situ hybridization using G248P88752A11 fosmid clone (green signal) and RP11–52401 control BAC clone (red) for the same 3 HapMap samples harboring 2, 3, and 4 copy genotypes are demonstrated in (D).

Variation_0316 association with age at onset (AAO) of Alzheimer disease in the discovery cohort

The discovery study is summarized in . The –logep values for Z scores from the hazard function regression performed on the array data using a 5-probe sliding window are plotted as a function of genomic location (A). In panel B, the –logep values are plotted against the variance (surrogate for allele frequency and number of alleles). The variance filter serves to exclude spurious association from a rare copy number variant not highly observed in the cohort and present in only one or a few individuals at the extremes of the AAO spectrum (B). (C) Age information and array data for AAO is represented in the red and blue color bar to the side of each array data heat map. Each cell in the subject age bar is adjacent to the row of the array data heat map for that subject. Red represents younger subjects, while blue represents older subjects in a linear scale from age 55 to age 84. The blue and yellow heat maps convey copy number array data for the region. Each blue-yellow row represents a subject and each column represents the data for a single oligonucleotide probe. Genomically adjacent oligos are shown next to each other from left to right.

Variation_0316 association with age at onset (AAO) of Alzheimer disease (AD) in the replication cohort

(A) Box plots depict the dosage association of the inferred copy number variant (CNV) variation_0316 (http://projects.tcag.ca/variation/) with AAO. There is an association of increased CN state with earlier AAO, the largest association signal emerging from the CN state 5+. (B) The corresponding survivorship curves for each of the groups depicted in the box plots. Subsequently, Cox proportional hazard regression was performed using the inferred CNV variation_0316 incorporating APOE and gender into the model. (C) Box plots show the dosage association with AAO, this time separating against the various APOE backgrounds. In each APOE class increased CN state is associated with earlier AAO, again the largest signal emerging from the CN state 5+. The time to event curves in (D) contrast the CN2 and CN3 states (red) with the CN5+ states (green) on the APOE N/4 (light) and APOE 4/4 (dark) backgrounds.